The aim of all projects in this application is to identify the mechanisms of resistance to BRAF inhibitors so that effective new therapies can be developed. The Biosample and Pathology Core (Core B) will provide access to melanoma biosamples (tissues and biofluids), cell lines and critical pathology services; together, these are essential to the success of the proposed projects. The Core will accomplish this by: Specific Aim 1. Provide well-characterized melanoma tissues, cell lines and short-term cultures from patients treated with BRAF inhibitors and prospectively develop additional cell lines from patient samples. The Core will be the repository for existing and prospectively collected melanoma tissues and cell lines, including those from patients treated with BRAF inhibitors. The BPC core also will deposit all isogenic pairs of parental BRAF inhibitor-sensitive and -resistant sublines derived in the laboratory, a proven model system to discover and mechanistically dissect acquired resistance pathways. All cell lines will be available to all four Projects and Core C for characterization and analyses. Specific Aim 2: Centralized performance of specialized pathology services. The Core prospectively will procure biosamples (tissues and biofluids) and maintain a web-based melanoma biorepository database (Daedalus Software) to permit live entry of samples at unlimited locations with customized clinical annotation. Standardized procedures ensure appropriate sample tracking/distribution, regulatory compliance (coordinated with Core A), and quality control. The Core will offer histology, immunohistochemistry, immunofluorescence, high throughput digital slide scanning and automated digital analysis. Testing will be developed for research and CLIA-certified settings. The Core will provide expert pathologic evaluation of therapeutic response during treatment and tissue/FNA quality standardization (e.g., percentage tumor content) for high throughput sequencing (Project 1) and microfluidic assisted diagnostics (Project 3). Specific Aim 3: Develop criteria to evaluate treatment response in cytology samples, including fine needle aspirations (FNAs). To foster Project 3 (develop new molecular techniques to evaluate molecular signaling and resistance signatures from small numbers of cells), we will determine the complementary histopathologic features of response (or lack thereof) on small samples so as to develop objective pathologic criteria of response. RELEVANCE (See instructions): All proposed projects require human melanoma biosamples and pathology services. This Core has banked tissues/cell lines from patients treated with BfRAF inhibitors and will continue to collect, track, prioritize and provide biosamples following national standards; pathology services (histology, immunohistochemistry, immunofluorescence, digital slide scanning and automated digital analysis) and diagnostic expertise also will be provided. These services would be extremely expensive to set up and run outside ofthe Core setting.